The present invention relates to methods and compositions for monitoring devices useful for determining whether patients have complied with prescribed therapeutic regimens. In particular, the detection devices of the present invention comprise instruments that may be placed on a patient""s skin for transdermal detection of a signal, such as a fluorescent signal, for indicating positive or negative compliance.
Nonadherence to therapy has been cited as one of the greatest obstacles to the elimination of certain infectious diseases such as tuberculosis (TB). Nonadherence results in treatment failure, relapse, continued infectiousness, and is one of the principal xe2x80x9cdriversxe2x80x9d for the emergence of drug-resistant strains of infectious agents.
Although numerous systems and procedures have been suggested and implemented in an attempt to improve drug therapy compliance, there remains a need for a system that is easily administered and simple to use. For example, xe2x80x9cDirectly Observed Treatment Short-Coursexe2x80x9d (DOTS), in which the ingestion of every dose of prescribed drugs is witnessed by a health care worker or other responsible individual, has been hailed by the World Health Organization (WHO) as the xe2x80x9cbreakthrough of the centuryxe2x80x9d because of its potential to ensure compliance. There are shortcomings to DOTS, however, including high cost, limited availability, patient resentment, and the requirement for a high degree of patient cooperation. Patients must faithfully attend a clinic or rendezvous with healthcare workers. Recent surveys of programs based on directly observed therapy indicate that they experience an average noncompliance rate of 18%. When patients fail to cooperate with directly observed therapy, involuntary incarceration is the final resort of health officials. Furthermore, each of the listed shortcomings are even more exaggerated in the developing world, where severe shortages in resources such as basic healthcare presents tremendous opportunity for the breeding and development of more drug-resistant and virulent strains of infectious agents. [1-3] In summary, although a variety of methods have been proposed to monitor compliance, including pill counting, microelectronic event monitoring system (MEMS) and other approaches [4-6], as of yet there is no easily administered system that ensures therapeutic compliance effectively and economically.
As valuable as directly observed therapy has proven to be, it requires the participation of several individuals and multiple procedures which in many cases makes therapy burdensome, resulting in ultimate non-compliance. Patients, physicians, and public health officials agree that more efficient ways to assure compliance are needed.
Recent scientific reporting has documented an alarming rise in infectious disease. Some diseases that were previously considered to be xe2x80x9cunder controlxe2x80x9d have re-emerged, many of them carried by drug-resistant strains making routine and standard therapeutic intervention useless. For example, it is well known that human infections caused by mycobacteria have been widespread since ancient times and that tuberculosis was a leading cause of death less than 250 years ago. What is less well known, however, is that mycobacterial diseases still constitute a leading cause of morbidity and mortality in countries with limited medical resources and can cause overwhelming, disseminated disease in immunocompromised patients. In fact, the number of reported tuberculosis cases has also been increasing in the developed world. What is even more troubling is that numerous drug-resistant mycobacterial strains have been identified.
Tuberculosis
Tuberculosis has been a major disease of mankind for most of recorded history. The incidence of the disease declined in parallel with advancing standards of living since at least the mid-nineteenth century. However, in spite of the efforts of numerous health organizations worldwide, the eradication of tuberculosis (TB) has never been achieved, nor is eradication imminent. Nearly half of the world""s population is infected with M. tuberculosis, with approximately 8 million new cases and 3 million deaths attributable to TB yearly.
After decades of decline, TB is on the rise. In the United States, up to 10 million individuals are believed to be infected. Almost 28,000 new cases were reported in 1990, a 9.4 percent increase over 1989. A sixteen percent increase was observed from 1985 to 1990. TB is acquired by the respiratory route when actively infected individuals spread this infection efficiently by coughing or sneezing xe2x80x9cdroplet nucleixe2x80x9d which contain viable bacilli. Overcrowded living conditions and shared air spaces are especially conducive to the spread of TB, underlying the increase in instances that have been observed in the U.S. in prison inmates and among the homeless in larger cities.
Alarmingly, outbreaks of TB cases resistant to at least two of the most effective anti-TB drugs rifampin (RFP) and isoniazide (INH) are being reported in hospitals and correctional facilities with evidence of transmission to human immunodeficiency virus (HIV) negative individuals. Approximately half the patients with acquired immune deficiency syndrome (AIDS) will acquire a mycobacterial infection, with TB being an especially devastating complication. AIDS patients are at higher risks of developing clinical TB and anti-TB treatment seems to be less effective. Consequently, the infection often progresses to a fatal disseminated disease.
The World Health Organization (WHO) continues to encourage the battle against TB, recommending prevention initiatives such as the xe2x80x9cExpanded Program on Immunizationxe2x80x9d (EPI), and as mentioned above, therapeutic compliance initiatives such as xe2x80x9cDirectly Observed Treatment Short-Coursexe2x80x9d (DOTS). For the eradication of TB, diagnosis, treatment, and prevention are equally important. Rapid detection of active TB patients will lead to early treatment by which about 90% cure is expected. Therefore, early diagnosis is critical for the battle against TB. Therapeutic compliance will ensure not only elimination of infection, but also reduction in the emergence of drug-resistance strains.
The emergence of drug-resistant M. tuberculosis is an extremely disturbing phenomenon. The rate of new TB cases proven resistant to at least one standard drug increased from 10 percent in the early 1980""s to 23 percent in 1991. Currently, seven percent of all cases of TB are resistant to at least one drug, over double the number from the early 1980. Compliance with therapeutic regimens, therefore, is a crucial component in efforts to eliminate TB and prevent the emergence of drug-resistant strains.
Although over 37 species of mycobacteria have been identified, more than 95% of all human infections are caused by six species of mycobacteria: M. tuberculosis, M. avium-intracellulare, M. kansasii, M. frotuitum, M. chelonae, and M. leprae. In addition, infections resulting from drug-resistant strains have also been observed.
The most prevalent mycobacterial disease in humans is tuberculosis (TB) which is caused by M. tuberculosis, M. bovis, or M. africanum (Merck Manual 1992). Infection is typically initiated by the inhalation of infectious particles which are able to reach the terminal pathways. Following engulfment by alveolar macrophages, the bacilli are able to replicate freely, with eventual destruction of the phagocytic cells. A cascade effect ensues wherein destruction of the phagocytic cells causes additional macrophages and lymphocytes to migrate to the site of infection, where they too are ultimately destructed. The disease is further disseminated during the initial stages by the infected macrophages which travel to local lymph nodes, as well as into the blood stream and other tissues such as the bone marrow, spleen, kidneys, bone and central nervous system. (See Murray et al. Medical Microbiology, The C.V. Mosby Company 219-230 (1990)).
Additionally, mycobacteria other than M. tuberculosis are also becoming increasingly problematic as elements in the list of opportunistic infections that plague the AIDS patient. Organisms from the Avium-intracellulare complex (MAC), especially serotypes four and eight, account for 68% of the mycobacterial isolates from AIDS patients. Enormous numbers of MAC are found (up to 1010 acid-fast bacilli per gram of tissue) and, consequently the prognosis for the infected AIDS patient is poor.
Mycobacteria, including Mycobacterium avium, are intracellular parasites that are capable of growth within the host in cells such as macrophages. The mycobacteria grow slowly, produce no endotoxin and are not motile. They multiply within the macrophages, kill the macrophage and are taken up by new macrophages to start the process over. Host resistance depends upon activation of the macrophages. Activated macrophages are able to kill the bacteria that reside within the cell. This activation depends upon specific T-cells which are produced as the result of a cell-mediated immune reaction against proteins of the mycobacteria. Mycobacterial infections have been likened to a war of attrition in which there is a delicate balance between the ability of the mycobacteria to survive within the macrophages and the ability of the host to activate macrophages sufficiently to kill them. In the absence of rapidly acting anti-infective compounds, the goal of therapy is to tip the balance in favor of the host.
There is still no clear understanding of the factors which contribute to the virulence of mycobacteria. Many investigators have implicated lipids of the cell wall and bacterial surface as contributors to colony morphology and virulence. Evidence suggests that C-mycosides, on the surface of certain mycobacterial cells, are important in facilitating survival of the organism within macrophages. Trehalose 6,6xe2x80x2 dimycolate, a cord factor, has been implicated for other mycobacteria.
Mycobacterium avium bacilli occur in several distinct colony forms. Bacilli which grow as transparent or rough colonies on conventional laboratory media are able to multiply within macrophages in tissue culture, are virulent when injected into susceptible mice, and are resistant to antibiotics. Rough or transparent bacilli which are maintained on laboratory culture media often spontaneously assume an opaque colony morphology at which time they fail to grow in macrophages, are avirulent in mice, and are highly susceptible to antibiotics. The differences in colony morphology between the transparent, rough and opaque strains of Mycobacterium avium are almost certainly due to the presence of a glycolipid coating on the surface of transparent and rough organisms which acts as a protective capsule. This capsule, or coating, is composed primarily of C-mycosides which apparently shield the virulent Mycobacterium avium organisms from lysosomal enzymes and antibiotics. By contrast, the non-virulent opaque forms of Mycobacterium avium have very little C-mycoside on their surface. Both resistance to antibiotics and resistance to killing by macrophages have been attributed to the glycolipid barrier on the surface of Mycobacterium avium. 
Diagnosis of TB is confirmed by the isolation and identification of the pathogen, although conventional diagnosis is based on sputum smears, chest X-ray examination (CXR), and clinical symptoms. Isolation of the mycobacteria on a medium takes as long a time as six to eight weeks. Species identification takes a further two weeks. There are several other techniques for detecting mycobacteria rapidly such as the polymerase chain reaction (PCR), mycobacterium tuberculosis direct test, or amplified mycobacterium tuberculosis direct test (MTD), and detection assays that utilize radioactive labels (2-5).
One diagnostic test that is widely used is the tuberculin skin test. Although numerous versions of the skin test are available, typically two preparations of tuberculin antigens are used: old tuberculin and purified protein derivative (PPD). The antigen is either injected into the skin intradermally, or is topically applied and then transdermally transported into the skin with the use of a multiprong inoculator (Tine test). Although developments have been made in the area of diagnosis and prevention of TB, there is still a need for improved methods for ensuring drug therapy compliance by infected individuals. Compliance is important not only effective for treatment and elimination of infection, it is also important for preventing the development of drug-resistant strains.
What is needed are inexpensive and accurate methods and compositions for determining whether patients have complied with prescribed therapeutic regimens. The methods and compositions should be simple and easily administered, and require minimum supervision. Preferably the detection system should not require involved analysis, such as chemical analysis of bodily fluids, rather, it should be a sensing device that monitors signals non-invasively. Additionally what is needed is a monitoring system for children who are often under the care of several adults making monitoring of therapeutic compliance both complicated and prone to errors such as duplicative administration of medication.
A compliance system that does not require the invasion of the skin surface of the tested person would minimize the exposure of the health care professional administering the test to the bodily fluids of the tested person and lessen the risk of transmission of other infectious agents that may be present in the tested person. A system that is easily implemented and has an easily determined positive or negative outcome is essential when monitoring compliance with a therapeutic regimen for highly infectious diseases such as tuberculosis, in individuals ranging from homeless persons and prison inmates, to schoolchildren and senior citizens.
Efficient and sensitive methods and compositions for the detection of compliance with therapeutic regimens are provided. In accordance with a preferred embodiment of the present invention, transdermal devices containing detection mechanisms are provided. Such transdermal devices are worn on the skin to detect ingestion of a drug and a signal is periodically generated to report whether or not the wearer has taken the drug. The signal may then be transmitted to a xe2x80x9creminder centerxe2x80x9d at a central location such as a public health facility, so that the patient can be prompted to take his medication if non-compliance is detected.
Unlike prior art detection methods, the detection methods provided herein are highly sensitive, easily administered and non-invasive. Most importantly, the detection methods are especially effective in transdermal detection of fluorescent signals, thereby eliminating the need for involved chemical analysis of bodily fluids, supervision by healthcare workers, or use of dangerous tracer substances such as radioactive labels.
The detection methods and compositions described herein comprise the incorporation of a detector, such as a fluorescent dye, in a drug, so that the detector can be monitored by a device comprising a transdermal instrument.
The detection methods and compositions described herein may optionally comprise features that enable filtration of interfering signals, data processing, data storage, timing devices, methods for signaling a patient to take medication, display panels and data recovery system. In addition, the detection methods and compositions described herein may further comprise a programming feature enabling the user to program drug schedules for prescribed medications. Importantly, the devices of the present invention may also comprise a security or tamper-proof feature that prevents unauthorized use of the device such as modification of settings, data input, or data analysis.
Accordingly, it is an object of the present invention to provide sensitive detection methods and compositions for monitoring compliance with therapeutic regimens.
It is another object of the present invention to provide sensitive detection methods and compositions that can be used transdermally.
It is yet another object of the present invention to provide sensitive detection methods and compositions for determining compliance with therapeutic regimens in order to remind patients to take their medication.
It is another object of the present invention to provide sensitive detection methods and compositions for creating a database of therapeutic compliance and emergence of drug-resistant infectious agents.
Yet another object of the present invention is to provide a kit for sensitive detection methods and compositions for monitoring therapeutic compliance.
It is another object of the present invention to provide sensitive detection methods and compositions for the monitoring of the clinical status of patients following therapy.
Another object of the present invention is to provide compositions and methods useful for monitoring therapeutic compliance in a variety of diseases and disorders, including, but not limited to infectious diseases, immunodeficiency diseases, cardiovascular disorders, pulmonary disorders, gastrointestinal, hepatic and biliary disorders, endocrine disorders, cancer, musculoskeletal and connective tissue disorders, neurologic and psychiatric disorders, genitourinary disorders and other physiological disorders and diseases.
Yet another object of the present invention is to provide compositions and methods useful for monitoring therapeutic compliance for therapeutic compositions comprising antimicrobial agents, antibiotics, antivirals, antidepressants, xcex2-lactam antibiotics, aminoglycosides, macrolides, lincomycin, clindamycin, tetracyclines, quinolones, polypeptides, sulfonamides, trimethoprims, sulfamethoxazoles, growth factors, lipids, neurotransmitters, vitamins, and minerals.
Another object of the present invention is to provide compositions and methods useful for monitoring therapeutic compliance for individuals participating in clinical trials and the like.
It is yet another object of the present invention to provide compositions and methods useful for monitoring therapeutic compliance in patients discretely and without revealing the patients"" illness.
Yet another object of the present invention to provide compositions and methods useful for monitoring therapeutic compliance in patients wherein the compliance device is capable of blanking and registration.
A further object of the present invention to provide compositions and methods useful for monitoring therapeutic compliance in patients in order to improve physician patient communication.
These and other objects, features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiments and the appended claims.